Three zinc(II) complexes of picolinic acid and its derivatives with a Zn(N2O2) coordination mode were prepared and evaluated for their insulinomimetic activities by in vitro and in vivo studies. By introducing an electron-donating methyl group into the picolinate ligand (pic), bis(6- or 3-methylpicolinato)zinc(II) complexes [Zn(6-mpa)2 or Zn(3-mpa)2, respectively] were prepared. The Zn(6-mpa)(2) complex was crystallized as a water adduct [Zn(6-mpa)2(H2O)].H2O, in which two carboxylate oxygens and two pyridine nitrogens of 6-mpa and a water oxygen coordinate to a zinc(II) with a trigonal bipyramidal geometry. By in vitro evaluation of the inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, the insulinomimetic activities of Zn(pic)2, Zn(6-mpa)2, and Zn(3-mpa)2 (IC50=0.64 +/- 0.13, 0.31 +/- 0.05, and 0.40 +/- 0.07 mM, respectively) were found to be higher than those of VOSO(4) (IC50=1.00 mM) and ZnSO(4) (IC50=1.58 +/- 0.05 mM) in terms of IC50 value, the 50% inhibition concentrations for the FFA release from the adipocytes. Then, Zn(6-mpa)2, which exhibited the highest in vitro insulinomimetic activity among three complexes examined, was given at a dose of 3.0 mg (45.9 micromol) Zn/kg body weight to KK-A(y) mice with type 2 diabetes mellitus by daily intraperitoneal injections for 14 days and it was found that the hereditary high blood glucose levels were lowered during the administration of the complex. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.

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Zinc(II) complexes with a Zn(O4) coordination mode were found to have insulinomimetic activity. A bis-maltolato zinc(II) (Zn(Mal)2) complex was revealed to be in an octahedral and a square pyramidal geometries in a unit cell. Both Zn(Mal)2 (IC50 = 0.59 mM) and bis-2-hydroxypyridine-N-oxide zinc(II) (IC50 = 0.41 mM) complexes exhibited higher insulinomimetic activity than VOSO4(IC50 = 1.00 mM) and ZnSO4(IC50 = 0.81 mM) in terms of IC50 values, which show 50% inhibition concentration of the complex in the free fatty acids release from rat adipocytes.

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Key words zinc(II) complex; amino acid; insulinomimetic activity; NIDDM; blood glucose normalizing effect; glucose tolerance test Zinc(II) ion is known to be one of the important essential trace elements found in biological systems and also in many metalloproteins and metalloenzymes which exist in living organisms. Physico-chemical properties of a zinc(II) ion, which functions as a Lewis acid, is entirely unlike those of vanadium ions with a redox property and insulinomimetic activity. Among many pharmacological and nutritional roles of zinc(II) ion, 1) an interesting pharmacological role was reported in 1980, in which a zinc(II) ion acts as an insulinomimics.2) The administration of ZnCl 2 to streptozotocininduced diabetes rats (STZ rats) or ob/ob mice normalized their high blood glucose levels, 3,4) when a high dose 3) and a long-term (8 weeks) administration were given. 4) However, the insulinomimetic activities of zinc(II) complexes have not yet been studied. Thus, we have tried to develop insulinomimetic zinc(II) complexes with various coordination modes around a zinc(II) ion, because zinc(II) ion is generally less toxic than vanadium ions. 5) During our investigation, we found first that zinc(II) maltolate complex with a Zn(O 4 ) coordination mode exibits high insulin-like activities in in vitro.6) On the basis of the results, we examined the structureactivity relationship of Zn(II) complexes, and found that zinc(II) complexes with Zn(N 2 O 2 ) coordination mode exibit higher insulinomimetic activity than those of ZnSO 4 and VOSO 4 . In this paper, we report the insulinomimic zinc(II) complexes with naturally occurring amino acids and their derivatives.The Zn(II) complexes used in this study were readily prepared by adding ZnSO 4 · 7H 2 O to an aqueous solution of lithium or barium salt of the appropriate ligand (generated in situ from ligands and lithium or barium hydroxide) at room temperature. The choice of lithium or barium as cation was made based upon the aqueous solubility of the desired complex. Lithium was preferred instead of barium, because the complex is prone to coprecipitate with barium sulfate in the reaction. All complexes were purified from hot water by recrystallization, identified by the elemental analyses and IR and 1 H-NMR spectra, and found to be molecular complexes without a counter ion.The insulinomimetic activities of the complexes were evaluated by using the isolated rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. 7)The inhibitory effects of the complexes were compared with those of ZnSO 4 and VOSO 4 as positive control. It was revealed that zinc(II) complexes with lower over-all stability constants (log b) than 10.5 exhibited higher insulinomimetic activities than those of ZnSO 4 and VOSO 4 or were comparable to them except Zn(GtG) (IC 50 ϭ3.18) ( Table 1). On the other hand, zinc(II) complexes with His, GeG, and mGeGm (log bϭ12.05, 11.22, and 11.83, respectively) with higher log b values than 11.0 showed essentially no insulinomimet...

A novel bis(L-carnitinato)Zn(II) complex, Zn(car) 2 Cl 2 , was prepared, and its insulinomimetic and antidiabetic activities were examined. The complex showed a tendency to lower the high blood glucose levels of KK-A y mice with type 2 diabetes mellitus when given by oral administration at a dose of 20 mg Zn/kg body weight for 16 d. In addition, the complex improved glucose tolerance ability when examined by the oral glucose tolerance test (1 g glucose/kg body weight).

In vitro insulinomimetic activities of Zn(II) complexes with three natural products, betaine, L-lactic acid, and D-(-)-quinic acid (qui), were found in rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. Based on the results, the blood glucose lowering effect in KK-A(y) mice with type 2 diabetes mellitus was observed by daily i.p. injections of a monomeric zinc(II) complex, Zn(qui)(2), for 13 d.

Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2 0 -deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.